Elucidating the hypoxia-inducible factor (HIF-1) response in gut barrier dysfunction and distant organ[unreadable] damage is the overall objective of this proposal. The studies proposed in this grant will test the following[unreadable] global hypothesis that persistence of the ischemia-induced HIF-1alpha response by intestinal bacteria and[unreadable] their products shifts the HIF-1alpha response from an adaptive/protective response to a potentially[unreadable] maladaptive/injurious one. Consequently, in this proposal, we will test the concept that the sustained HIF-[unreadable] 1cc response in the gut acts as an effector in ischemia/reperfusion-mediated gut injury and the production of[unreadable] gut derived factors, thereby playing a role in gut-induced distant organ damage. By providing potentially[unreadable] important mechanistic information on the pathogenesis of T/HS-induced gut injury, the results obtained from[unreadable] our studies will help clarify key issues of the Center Grant's first global hypothesis, which is that gut-derived[unreadable] factors present in the mesenteric lymph of the ischemic gut contribute to distant organ injury. Additionally,[unreadable] the experiments proposed in our Specific Aims will contribute to the Center Grant's second major hypothesis[unreadable] by testing whether the resistance of proestrus female rats to T/HS-induced gut injury is associated with a[unreadable] differential HIF-1 intestinal response and that the intestinal HIF-1 response to T/HS is. at least in part.[unreadable] modulated by sex hormones. Aim 1 will elucidate the functional significance of l/R-mediated elevations of[unreadable] intestinal HIF-1 in vivo as well as the role of intestinal bacteria in prolonging the intestinal HIF-1 response.[unreadable] The effects of T/HS-induced gut injury, gut inflammation and acute lung injury will be examined in partially[unreadable] deficient HIF-1alpha+/- and HIF-1+/+ WT mice. To further evaluate the effect of intestinal bacteria on the HIF-1[unreadable] response, intestinal antibiotic decontamination and bacterial overgrowth male rat T/HS models will be[unreadable] employed. The effects of partial HIF-1alpha deficiency on gut injury and inflammation will also be tested in the[unreadable] intestinal bacterial overgrowth and antibiotic decontaminated T/HS models. Aim 2 will test whether[unreadable] overexpression or inhibition of HIF-1 in enterocytic cell lines affects gut barrier function and gut inflammation[unreadable] utilizing enterocytic cell lines. Aim 3 will elucidate the mechanisms by which enteric bacteria or LPS regulate[unreadable] HIF-1 activation in enterocytes under normoxic conditions. Specifically, experiments will determine whether[unreadable] regulation of HIF-1 is via the activation of MARK, Akt or NO. Aim 4 will test the hypothesis that the[unreadable] resistance of proestrus female rats to T/HS-induced gut injury is associated with a blunted intestinal HIF-1 a[unreadable] response. A deeper insight of the intestinal HIF-1 response will identify potential targets for therapeutic[unreadable] intervention at the onset of intestinal ischemia.[unreadable]